5-[4-(Benzyloxy)phenyl]-1,3,4-oxadiazol-2(3H)-one derivatives and related analogues: New reversible, highly potent, and selective monoamine oxidase type B inhibitors

Article abstract of DOI:10.1021/jm00061a006

Thirty-three new 5-[4-(benzyloxy)phenyl]-1,3,4-oxadiazol-2(3H)-one derivatives including related analogues, designed as inhibitors of monoamine oxidase type B (MAO B), were synthesized and investigated both in vitro and ex vivo for their abilities to inhibit selectively rat brain MAO B over MAO A. Three inhibitors were found to act as reversible, highly potent, and selective MAO B inhibitors, namely the nitrile derivative 5-[4- (benzyloxy)phenyl]-3-(2-cyanoethyl)-1,3,4-oxadiazol-2(3H)-one (12a) and two closely related homologues, the corresponding oxadiazolethione 13a and the alcohol 14b. Their IC₅₀(MAO B) values are in the low nanomolar range of 1.4-4.6 nM and their selectivities, estimated by the ratio of IC₅₀ values (A/B), are from 3200 to >71 400. Compound 12a exhibited the highest activity against MAO B. Its IC₅₀ was evaluated to be 1.4 nM with a quasitotal selectivity (>71 400) toward this enzyme. In ex vivo studies, 12a showed a reversible and short duration of action. MAO B was markedly inhibited with the oral dose of 1 mg/kg without any alteration of MAO A, and the inhibition almost did not exceed 24 h. Its ED₅₀ (1 h after oral administration) was evaluated to be 0.56 mg (1.7 μmol)/kg. Remarkably, MAO A was not affected at doses as high as 1500 mg/kg, po. In addition, no apparent toxicity or behavioral anomaly was observed during the treatment even at the maximum administrated dose. SAR studies emphasize the existence of three binding sites to the enzyme with a special importance of the terminal phenyl. Analysis of the inhibition kinetics indicated that 12a acts in a two-step mechanism as a competitive, slow, and tight-binding inhibitor of MAO B with a K(i) value of 0.22 μM and an overall K(i)* value at equilibrium of 0.7 nM.